Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.

We investigated the expression of the proinflammatory cytokine interleukin (IL)-17 in cardiac fibroblasts and its induction by high glucose (HG). Our results show that primary mouse cardiac fibroblasts (mCFs) secrete low basal levels of IL- 17 and that HG (25 mM n-glucose) as opposed to low glucose (5 mM n-glucose + 20 mM mannitol) significantly enhances its secretion. HG induces IL- 17 mRNA expression by both transcriptional and posttranscriptional mechanisms. HG induces phosphoinositide 3- kinase [P13K; inhibited by adenoviral (Ad).dominant negative (dn)PI3Kp85I, Akt (inhibited by Ad.dnAktl), and ERK (inhibited by PD-98059) activation and induces IL-17 expression via P13K→Akt→ERK-dependent signaling. Moreover, mCFs express both IL-17 receptors A and C, and although IL-17RA is upregulated, HG fails to modulate IL-17RC expression. Furthermore, IL-17 stim- ulates net collagen production by mCFs. Pretreatment with the phytoalexin resveratrol blocks HG-induced P13K-, Akt-, and ERK-dependent IL-17 expression. These results demonstrate that 1) cardiac fibroblasts express IL-17 and its receptors; 2) HG upregulates IL-17 and IL-17RA, suggesting a positive amplification loop in IL-17 signaling in hyperglycemia; 3) IL- 17 enhances net collagen production; and 4) resveratrol can inhibit these HG-induced changes. Thus, in hyperglycemic conditions, IL- 17 may potentiate myocardial inflammation, injury, and remodeling through autocrine and paracrine mechanisms, and resveratrol has therapeutic potential in ameliorating this effect. [ABSTRACT FROM AUTHOR]